High-potency ligands for DREADD imaging and activation in rodents and monkeys

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N- oxide (CNO) lacks brain entry a...

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Bibliographic Details
Published in:	Nature communications Vol. 10; no. 1; pp. 4627 - 12
Main Authors:	Bonaventura, Jordi, Eldridge, Mark A. G., Hu, Feng, Gomez, Juan L., Sanchez-Soto, Marta, Abramyan, Ara M., Lam, Sherry, Boehm, Matthew A., Ruiz, Christina, Farrell, Mitchell R., Moreno, Andrea, Galal Faress, Islam Mustafa, Andersen, Niels, Lin, John Y., Moaddel, Ruin, Morris, Patrick J., Shi, Lei, Sibley, David R., Mahler, Stephen V., Nabavi, Sadegh, Pomper, Martin G., Bonci, Antonello, Horti, Andrew G., Richmond, Barry J., Michaelides, Michael
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 11-10-2019 Nature Publishing Group Nature Portfolio
Subjects:	59/78 631/1647/245/2092 631/378/3920 631/92 639/638/309/436 64/110 64/60 82/1 96/10 96/106 96/109 96/47 96/95 Agonists Animals Basic converters Binding sites Brain Brain research Clozapine Clozapine - analogs & derivatives Clozapine - chemistry Designer Drugs Drug abuse Drug dosages Fluorine isotopes Fluorine Radioisotopes - analysis Haplorhini HEK293 Cells Humanities and Social Sciences Humans Laboratory animals Ligands Mapping Medicine Monkeys multidisciplinary Neuroanatomical Tract-Tracing Techniques - methods Neuroimaging Neuronal Tract-Tracers - analysis Neuronal Tract-Tracers - chemistry Neurosciences Positron emission Positron emission tomography Positron-Emission Tomography - methods Radioactive tracers Receptors Rodentia Rodents Science Science (multidisciplinary) Tomography
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Summary:	Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N- oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18 F positron emission tomography (PET) DREADD radiotracer, [ 18 F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [ 18 F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a powerful tool for neuroscience, but the standard DREADD ligand, CNO, has significant drawbacks. Here the authors report two novel high-potency DREADD ligands and a novel DREADD radiotracer for imaging purposes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-12236-z